Digenic loci and novel variants involved in thyroid hormone synthesis: evidence from congenital hypothyroidism cases

Congenital hypothyroidism (CH) is the most neonatal metabolic disorder and results in severe neurodevelopmental impairment and infertility if untreated early and effectively. The inheritance of CH is controversial. Though it has been understood to be a monogenic disorder, more and more cases were found to harbor heterozygous at two of pathogenic gene simultaneously as a digenic form. Here, we reported 10 permanent congenital hypothyroidism (PCH) cases with digenic variants at two of this 5 genes, TSHR, TG, TPO, DUOX2 and DUOXA2, which are involved in the same metabolic pathway- thyroid hormone biosynthesis.Additionally, seven novel variants were identified as TSHR c.679G>A (p.G227R); DUOX2 c.127A>T (p.N43Y), c.608-619del (p.L203-P207delinsP) and c.959T>C (p.L320P); TG c.2307G>A (p.W769*) and c.6759_6765del (p.S2254Mfs*88); DUOXA2 c.93T>G (p.F31L). The data present here will extend our awareness of complex inheritance pattern in CH.